PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.     

Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry — Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort

Introduction

Phosphatase and tensin homolog (PTEN) loss is frequently observed in NSCLC and associated with both phosphoinositide 3-kinase activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable readout, but lacks standardized staining protocol and cutoff value.

Hernia formation after single‐stage umbilical vein marsupialization in three Percheron foals diagnosed with septic omphalophlebitis

Septic omphalophlebitis is a common disease process with a variety of morbidities and possible mortality. Affected umbilical remnant resection is highly successful but may not always be possible. Umbilical marsupialization can be implemented when total resection cannot be accomplished with minimally reported complications. Umbilical vein marsupialization was performed on three Percheron foals with extensive septic omphalophlebitis using the one‐stage paramedian translocation technique and prolonged postoperative antimicrobial therapy. Long‐term follow‐up revealed herniation at the marsupialization site in all foals. Two foals were subsequently treated with herniorrhaphy at the prior marsupialization site. One foal died due to septic peritonitis with hernia formation 3 months after marsupialization. This case series highlights hernia formation as a potential complication following one‐stage umbilical vein marsupialization in foals diagnosed with septic omphalophlebitis and should be considered as a possible postoperative complication.     

Comparing single‐target and multitarget approaches for postoperative circulating tumour DNA detection in stage II–III colorectal cancer patients

Circulating tumour DNA (ctDNA) detection for postoperative risk stratification in cancer patients has great clinical potential. However, low ctDNA abundances complicates detection. Multitarget (MT) detection strategies have been developed to increase sensitivity. Yet, empirical evidence supporting performance gains of MT vs. single‐target (ST) strategies in a postoperative setting is limited. We compared ctDNA detection in 379 paired plasma samples from 112 stage II–III colorectal cancer patients by ST digital PCR and MT sequencing of 16 patient‐specific variants. The strategies exhibited good concordance (90%, Cohen''s Kappa 0.79), with highly correlated ctDNA quantifications (Pearson r = 0.985). A difference was observed in ctDNA detection preoperatively (ST 72/92, MT 88/92). However, no difference was observed immediately after surgery in recurrence (ST 11/22, MT 10/22) or nonrecurrence (both 2/34) patients. In serial samples, detection was similar within recurrence (ST 13/16, MT 14/16) and nonrecurrence (ST 3/49, MT 1/49) patients. Both approaches yielded similar lead times to standard‐of‐care radiology (ST 4.0 months, MT 4.1 months). Our findings do not support significant performance gains of the MT strategy over the ST strategy for postoperative ctDNA detection.     

Comparison of dose requirement,serum erythropoietin and blood pressure following intravenous and subcutaneous erythropoietin treatment of dialysis patients IV and SC erythropoietin

Objective: The purpose of the study was to investigate the effect of route of administration of erythropoietin (EPO) on the dose requirement in dialysis patients after intravenous (IV) and subcutaneous (SC) therapy. Methods: The study was performed as a single centre, prospective, open, combined parallel and cross-over study of 50 dialysis patients, consecutively randomised to IV or SC treatment with EPO. The initial dose was 40 U⋅kg⁻¹ 3-times weekly, adjusted to increase haemoglobin (Hgb) from a median 5.3 mmol⋅l⁻¹ to a target of haemoglobin 6.5–7.5 mmol⋅l⁻¹. After reaching the target level, the haemoglobin was maintained for 4 months (Period 1). Then IV and SC treatment was switched for a further 4 months (Period 2). The study included high risk patients. The adjustment period was completed by 38 patients, Period one by 32 patients (IV/SC = 15/17; male/female = 19/13; age = 54 (24– 71) y), and Period two by 22 patients. Results: No significant difference was found between the two groups in the reticulocyte response, the rate of Hgb increase (IV 0.7 versus SC 0.5, mmol⋅l⁻¹⋅ month⁻¹), time to reach target level (IV 43 versus SC 60 days), or total EPO dose per increase in haemoglobin to target level (IV 663 versus SC 946 (U⋅kg⁻¹) per (mmol Hgb⋅l⁻¹). The overall median maintenance dose during the last month of the two four month periods was 105 (range IV 51–336) U⋅kg⁻¹⋅w⁻¹ and SC 104 (range 21–321) U⋅kg⁻¹⋅w⁻¹. Trough serum EPO levels were significantly higher during SC treatment. The blood pressure did not change significantly from the base level after either route of administration; start 133/80 versus 143/80 mmHg, target 127/78 versus 154/85 mmHg, and maintenance period 140/84 versus 142/85 mmHg. Thus, three-times weekly IV or SC EPO did not differ significantly in efficacy or in the effect on blood pressure in dialysis patients. Received: 13 June 1995/Accepted in revised form: 30 October 1995